Blood Res.  2023 Dec;58(4):166-172. 10.5045/br.2023.2023177.

Recent advances in cellular immunotherapy for lymphoid malignancies

• Chung H
• Cho H

• KMID: 2550193
• DOI: http://doi.org/10.5045/br.2023.2023177

Abstract

Cellular immunotherapy with chimeric antigen receptor (CAR) T-cells has revolutionized the treatment of lymphoid malignancies. This review addresses the need for CAR expression in our endogenous T-cells to kill tumor cells with a focus on the basic principles of T-cell receptor recognition of major histocompatibility complex-peptide complexes. We review the factors associated with CAR T-cell outcomes and recent efforts to employ CAR T-cells in earlier lines of therapy. We also discuss the value of bispecific T-cell engagers as off-the-shelf products with better toxicity profiles. Finally, natural killer cells are discussed as an important cellular immunotherapy platform with the potential to broaden immunotherapeutic applications beyond lymphoid malignancies.

Keyword

Cellular immunotherapy; Chimeric antigen receptor T cells; Lymphoma; Multiple myeloma

Reference

1. Alaggio R, Amador C, Anagnostopoulos I, et al. 2022; The 5th edition of the World Health Organization Classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 36:1720–48. DOI: 10.1038/s41375-022-01620-2. PMID: 35732829. PMCID: PMC9214472.

2. Campo E, Jaffe ES, Cook JR, et al. 2022; The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 140:1229–53. DOI: 10.1182/blood.2022015851. PMID: 35653592. PMCID: PMC9479027.

3. Yi JH, Jeong SH, Kim SJ, et al. 2023; Outcomes in refractory diffuse large B-cell lymphoma: results from two prospective Korean cohorts. Cancer Res Treat. 55:325–33. DOI: 10.4143/crt.2022.008. PMID: 35468269. PMCID: PMC9873324.

4. Dunleavy K. 2021; Double-hit lymphoma: optimizing therapy. Hematology Am Soc Hematol Educ Program. 2021:157–63. DOI: 10.1182/hematology.2021000247. PMID: 34889402. PMCID: PMC8791152.

5. Weiner GJ. 2010; Rituximab: mechanism of action. Semin Hematol. 47:115–23. DOI: 10.1053/j.seminhematol.2010.01.011. PMID: 20350658. PMCID: PMC2848172.

6. Kim KH, Kim CG, Shin EC. 2020; Peripheral blood immune cell-based biomarkers in anti-PD-1/PD-L1 therapy. Immune Netw. 20:e8. DOI: 10.4110/in.2020.20.e8. PMID: 32158596. PMCID: PMC7049582.

7. Philip M, Schietinger A. 2022; CD8⁺ T cell differentiation and dysfunction in cancer. Nat Rev Immunol. 22:209–23. DOI: 10.1038/s41577-021-00574-3. PMID: 34253904. PMCID: PMC9792152.

8. Neefjes J, Jongsma ML, Paul P, Bakke O. 2011; Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 11:823–36. DOI: 10.1038/nri3084. PMID: 22076556.

9. Rock KL, Reits E, Neefjes J. 2016; Present yourself! By MHC class I and MHC class II molecules. Trends Immunol. 37:724–37. DOI: 10.1016/j.it.2016.08.010. PMID: 27614798. PMCID: PMC5159193.

10. Burger JA, Wiestner A. 2018; Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer. 18:148–67. DOI: 10.1038/nrc.2017.121. PMID: 29348577.

11. Labanieh L, Mackall CL. 2023; CAR immune cells: design principles, resistance and the next generation. Nature. 614:635–48. DOI: 10.1038/s41586-023-05707-3. PMID: 36813894.

12. Holliger P, Hudson PJ. 2005; Engineered antibody fragments and the rise of single domains. Nat Biotechnol. 23:1126–36. DOI: 10.1038/nbt1142. PMID: 16151406.

13. Larson RC, Maus MV. 2021; Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer. 21:145–61. DOI: 10.1038/s41568-020-00323-z. PMID: 33483715. PMCID: PMC8353572.

14. Kawalekar OU, O' Connor RS, Fraietta JA, et al. 2016; Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 44:712. DOI: 10.1016/j.immuni.2016.02.023. PMID: 28843072.

15. Selli ME, Landmann JH, Terekhova M, et al. 2023; Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction. Blood. 141:3153–65. DOI: 10.1182/blood.2023020100. PMID: 37130030.

16. Bachy E, Le Gouill S, Di Blasi R, et al. 2022; A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med. 28:2145–54. DOI: 10.1038/s41591-022-01969-y. PMID: 36138152. PMCID: PMC9556323.

17. Bethge WA, Martus P, Schmitt M, et al. 2022; GLA/DRST real-world outcome analysis of CAR T-cell therapies for large B-cell lymphoma in Germany. Blood. 140:349–58. DOI: 10.1182/blood.2021015209. PMID: 35316325.

18. Gauthier J, Gazeau N, Hirayama AV, et al. 2022; Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL. Blood. 139:3722–31. DOI: 10.1182/blood.2021014497. PMID: 35439295. PMCID: PMC9247364.

19. Cappell KM, Kochenderfer JN. 2023; Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 20:359–71. DOI: 10.1038/s41571-023-00754-1. PMID: 37055515. PMCID: PMC10100620.

20. Locke FL, Rossi JM, Neelapu SS, et al. 2020; Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4:4898–911. DOI: 10.1182/bloodadvances.2020002394. PMID: 33035333. PMCID: PMC7556133.

21. Majzner RG, Mackall CL. 2018; Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8:1219–26. DOI: 10.1158/2159-8290.CD-18-0442. PMID: 30135176.

22. Spiegel JY, Patel S, Muffly L, et al. 2021; CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 27:1419–31. DOI: 10.1038/s41591-021-01436-0. PMID: 34312556. PMCID: PMC8363505.

23. Cordoba S, Onuoha S, Thomas S, et al. 2021; CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nat Med. 27:1797–805. DOI: 10.1038/s41591-021-01497-1. PMID: 34642489. PMCID: PMC8516648.

24. Roddie C, Lekakis LJ, Marzolini MAV, et al. 2023; Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma. Blood. 141:2470–82. DOI: 10.1182/blood.2022018598. PMID: 36821767. PMCID: PMC10646794.

25. Tantalo DG, Oliver AJ, von Scheidt B, et al. 2021; Understanding T cell phenotype for the design of effective chimeric antigen receptor T cell therapies. J Immunother Cancer. 9:e002555. DOI: 10.1136/jitc-2021-002555. PMID: 34035114. PMCID: PMC8154965. PMID: f9c49c34a89349f48727b7149be0e6a6.

26. Biasco L, Izotova N, Rivat C, et al. 2021; Clonal expansion of T memory stem cells determines early anti-leukemic responses and long- term CAR T cell persistence in patients. Nat Cancer. 2:629–42. DOI: 10.1038/s43018-021-00207-7. PMID: 34345830. PMCID: PMC7611448.

27. Melenhorst JJ, Chen GM, Wang M, et al. 2022; Decade-long leukaemia remissions with persistence of CD4⁺ CAR T cells. Nature. 602:503–9. DOI: 10.1038/s41586-021-04390-6. PMID: 35110735. PMCID: PMC9166916.

28. Cohen AD, Garfall AL, Stadtmauer EA, et al. 2019; B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 129:2210–21. DOI: 10.1172/JCI126397. PMID: 30896447. PMCID: PMC6546468.

29. Garfall AL, Dancy EK, Cohen AD, et al. 2019; T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 3:2812–5. DOI: 10.1182/bloodadvances.2019000600. PMID: 31575532. PMCID: PMC6784521.

30. Lin Y, Raje NS, Berdeja JG, et al. 2023; Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial. Nat Med. 29:2286–94. DOI: 10.1038/s41591-023-02496-0. PMID: 37592106. PMCID: PMC10504071.

31. Turtle CJ, Hanafi LA, Berger C, et al. 2016; CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 126:2123–38. DOI: 10.1172/JCI85309. PMID: 27111235. PMCID: PMC4887159.

32. Abramson JS, Palomba ML, Gordon LI, et al. 2020; Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 396:839–52. DOI: 10.1016/S0140-6736(20)31366-0. PMID: 32888407.

33. Westin JR, Oluwole OO, Kersten MJ, et al. 2023; Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 389:148–57. DOI: 10.1056/NEJMoa2301665. PMID: 37272527.

34. Houot R, Bachy E, Cartron G, et al. 2023; Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial. Nat Med. 29:2593–601. DOI: 10.1038/s41591-023-02572-5. PMID: 37710005. PMCID: PMC10579056.

35. Neelapu SS, Dickinson M, Munoz J, et al. 2022; Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 28:735–42. DOI: 10.1038/s41591-022-01731-4. PMID: 35314842. PMCID: PMC9018426.

36. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. 2023; Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 388:1002–14. DOI: 10.1056/NEJMoa2213614. PMID: 36762851.

37. San-Miguel J, Dhakal B, Yong K, et al. 2023; Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 389:335–47. DOI: 10.1056/NEJMoa2303379. PMID: 37272512.

38. Byun JM. 2023; Practical issues in CAR T-cell therapy. Blood Res. 58(S1):S11–2. DOI: 10.5045/br.2023.2023015. PMID: 36843380. PMCID: PMC10133847.

39. Jain MD, Smith M, Shah NN. 2023; How I treat refractory CRS and ICANS after CAR T-cell therapy. Blood. 141:2430–42. DOI: 10.1182/blood.2022017414. PMID: 36989488. PMCID: PMC10329191.

40. Mikhael J, Fowler J, Shah N. 2022; Chimeric antigen receptor T-cell therapies: barriers and solutions to access. JCO Oncol Pract. 18:800–7. DOI: 10.1200/OP.22.00315. PMID: 36130152.

41. Song F, Hu Y, Zhang Y, et al. 2023; Safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy for patients with relapsed/refractory B-ALL. J Immunother Cancer. 11:e005701. DOI: 10.1136/jitc-2022-005701. PMID: 36808074. PMCID: PMC9944646. PMID: ac4f46e455c1416b9ec04d48604e345b.

42. Moon D, Tae N, Park Y, Lee SW, Kim DH. 2022; Development of bispecific antibody for cancer immunotherapy: focus on T cell engaging antibody. Immune Netw. 22:e4. DOI: 10.4110/in.2022.22.e4. PMID: 35291652. PMCID: PMC8901699.

43. Lindner SE, Johnson SM, Brown CE, Wang LD. 2020; Chimeric antigen receptor signaling: functional consequences and design implications. Sci Adv. 6:eaaz3223. DOI: 10.1126/sciadv.aaz3223. PMID: 32637585. PMCID: PMC7314561.

44. Goebeler ME, Bargou RC. 2020; T cell-engaging therapies - BiTEs and beyond. Nat Rev Clin Oncol. 17:418–34. DOI: 10.1038/s41571-020-0347-5. PMID: 32242094.

45. Jen EY, Xu Q, Schetter A, et al. 2019; FDA approval: blinatumomab for patients with B-cell precursor acute lymphoblastic leukemia in morphologic remission with minimal residual disease. Clin Cancer Res. 25:473–7. DOI: 10.1158/1078-0432.CCR-18-2337. PMID: 30254079.

46. Moreau P, Garfall AL, van de Donk NWCJ, et al. 2022; Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 387:495–505. DOI: 10.1056/NEJMoa2203478. PMID: 35661166. PMCID: PMC10587778.

47. Lesokhin AM, Tomasson MH, Arnulf B, et al. 2023; Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 29:2259–67. DOI: 10.1038/s41591-023-02528-9. PMID: 37582952. PMCID: PMC10504075.

48. Chari A, Minnema MC, Berdeja JG, et al. 2022; Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 387:2232–44. DOI: 10.1056/NEJMoa2204591. PMID: 36507686.

49. Budde LE, Sehn LH, Matasar M, et al. 2022; Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 23:1055–65. DOI: 10.1016/S1470-2045(22)00335-7. PMID: 35803286.

50. Hutchings M, Mous R, Clausen MR, et al. 2021; Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 398:1157–69. DOI: 10.1016/S0140-6736(21)00889-8. PMID: 34508654.

51. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. 2022; Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 387:2220–31. DOI: 10.1056/NEJMoa2206913. PMID: 36507690.

52. Zhu WM, Middleton MR. 2023; Combination therapies for the optimisation of bispecific T-cell engagers in cancer treatment. Immunother Adv. 3:ltad013. DOI: 10.1093/immadv/ltad013. PMID: 37599903. PMCID: PMC10439528.

53. Laskowski TJ, Biederstädt A, Rezvani K. 2022; Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 22:557–75. DOI: 10.1038/s41568-022-00491-0. PMID: 35879429. PMCID: PMC9309992.

54. Wolf NK, Kissiov DU, Raulet DH. 2023; Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol. 23:90–105. DOI: 10.1038/s41577-022-00732-1. PMID: 35637393.

55. Gong Y, Klein Wolterink RGJ, Wang J, Bos GMJ, Germeraad WTV. 2021; Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hematol Oncol. 14:73. DOI: 10.1186/s13045-021-01083-5. PMID: 33933160. PMCID: PMC8088725. PMID: 6c31255476e94becb8ad5d79bda37f27.

56. Duan S, Guo W, Xu Z, et al. 2019; Natural killer group 2D receptor and its ligands in cancer immune escape. Mol Cancer. 18:29. DOI: 10.1186/s12943-019-0956-8. PMID: 30813924. PMCID: PMC6391774. PMID: 152bb4d4c36846b1a0d83bca422c28e8.

57. Leivas A, Valeri A, Córdoba L, et al. 2021; NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma. Blood Cancer J. 11:146. DOI: 10.1038/s41408-021-00537-w. PMID: 34392311. PMCID: PMC8364555. PMID: 1628f0cb7aff4d6990b48e1fdfb3acb4.

58. Chiossone L, Dumas PY, Vienne M, Vivier E. 2018; Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol. 18:671–88. DOI: 10.1038/s41577-018-0061-z. PMID: 30209347.

59. Du C, Bevers J 3rd, Cook R, et al. 2019; MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner. J Immunother Cancer. 7:207. DOI: 10.1186/s40425-019-0687-9. PMID: 31387641. PMCID: PMC6685158. PMID: ff8ffe1b8bda435d9db38f1f06d4754c.

60. Dhar P, Wu JD. 2018; NKG2D and its ligands in cancer. Curr Opin Immunol. 51:55–61. DOI: 10.1016/j.coi.2018.02.004. PMID: 29525346. PMCID: PMC6145810.

61. Cho H, Kim KH, Lee H, et al. 2021; Adaptive natural killer cells facilitate effector functions of daratumumab in multiple myeloma. Clin Cancer Res. 27:2947–58. DOI: 10.1158/1078-0432.CCR-20-3418. PMID: 33602683.

62. Bigley AB, Spade S, Agha NH, et al. 2021; FcεRIγ-negative NK cells persist in vivo and enhance efficacy of therapeutic monoclonal antibodies in multiple myeloma. Blood Adv. 5:3021–31. DOI: 10.1182/bloodadvances.2020002440. PMID: 34357379. PMCID: PMC8361460.

63. Maddineni S, Silberstein JL, Sunwoo JB. 2022; Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells. J Immunother Cancer. 10:e004693. DOI: 10.1136/jitc-2022-004693. PMID: 35580928. PMCID: PMC9115029. PMID: 03fe7b47c33b4dbda2f515ddb7c2dac7.